Several clinical studies are performed to determine objective and subjective measures associated with smoking and tobacco withdrawal. The results of these studies are applied to develop paradigms for testing of drugs for the treatment of nicotine withdrawal. Neurophysiologic data indicate that nicotine acts on neural substrates involved in attention, cognition and memory. For example, the effects of mecamylamine, a centrally acting nicotinic antagonist is studied to determine the contribution of tonic cholinergic mechanisms on the EEG and cognitive tasks in smokers and nonsmokers. The ability of transcranially delivered electrostimulation to alleviate nicotine withdrawal was evaluated in a treatment protocol. The efficacy of transdermally delivered nicotine to diminish signs and symptoms of tobacco spontaneous withdrawal are tested in a residential study. The effects of nicotine withdrawal on delayed auditory feedback - a proposed measure of attention and distraction - is being evaluated. The interaction of caffeine and nicotine after overnight abstinence was assessed. Dependent measures for these studies include: Gordon vigilance task (with and without distracters), word memory, PAB (performance) spontaneous EEG, evoked potentials, blood pressure, heart rate (physiologic); withdrawal scales, craving, drug liking, drug identification (subjective). Studies on the effects of smokeless tobacco products, and a newly developed denicotinized cigarette are completed. In an ongoing project, the effects of cigarettes that deliver nicotine from placebo cigarettes were tested in a spaced-smoking paradigm. In another study, the effects of the denicotinized cigarettes in a rapid smoking procedure are evaluated. Genetic mechanisms involved in the effect and appeal of cigarette smoking and tobacco withdrawal are investigated. These studies contribute to an understanding of the mechanisms of nicotine addiction and are also of practical value in the development of more effective medications for treating nicotine dependence and withdrawal.